While haloperidol exhibits pharmacological activity at a number of receptors in the brain, it exerts its antipsychotic effects through its potent antagonism of the dopamine receptor (mainly D2), particularly in the mesolimbic and mesocortical systems of the brain. It also binds to α1-receptors and, at higher doses, to 5-HT2-receptors.
Haloperidol is a highly lipophilic compound and is highly metabolized in humans, which may cause wide interindividual variability in its pharmacokinetics. Haloperidol is well absorbed from the gastrointestinal tract when taken orally, but the first-pass effect reduces oral bioavailability to 40-75%. Enzymes involved in the biotransformation of haloperidol include CYP3A4 and CYP2D6 and carbonyl reductase. Plasma protein binding is only about 10%. After oral administration, the half-life is approximately 14.5-36.7 hours. After intramuscular injection, the mean half-life is 20.7 hours. Haloperidol and its metabolites are almost entirely excreted in the urine.
Interactions, some of which may be threatening, may occur with the following drugs:
- Amiodarone: QT interval prolongation.
- levodopa: reduced effect of levodopa
- Methyldopa: increased risk of extrapyramidal side effects and other adverse central effects
- Other centrally depressant drugs (alcohol, tranquilizers, narcotics): effects and side effects of these drugs (sedation, respiratory depression) are increased. In particular, doses of concomitant opioids may be reduced by 50% for chronic pain.
- Other drugs metabolized by the CYP3A4 enzyme system: Inducers such as carbamazepine, phenobarbital and rifampicin decrease plasma levels and inhibitors such as quinidine and fluoxetine increase plasma levels.
Trizyklische Antidepressiva: Metabolismus und Elimination von Trizyklika signifikant vermindert, erhöhte Toxizität festgestellt (anticholinerge und kardiovaskuläre Nebenwirkungen, Absenkung der Krampfschwelle